I'm a pharmacologist, freelance science and medical writer, educator, and speaker with a passion for public understanding of science and medicine. I earned a Ph.D. in pharmacology and therapeutics from the University of Florida and a B.S. in toxicology from the Philadelphia College of Pharmacy and Science. I report on all things pharmaceutical and scientific from the Research Triangle Park area of North Carolina.

A federal corruption probe involving a prominent U.S. governor and his wife over potential gifts from a wealthy CEO of a dietary supplement company?

So what do I find most interesting?

What’s in those supplements that facilitated the CEO’s wealth?

Last week, former Virginia governor Robert F. McDonnell and his wife, Maureen, were indicted for allegedly accepting “loans and gifts of money, clothes, golf fees and equipment, trips, and private plane rides” valued at $165,000 from Jonnie R. Williams, Sr., former CEO of Star Scientific.

The 43-page indictment includes the charge that Williams’ support would in turn garner favor from the governor’s office for his Glen Allen, Virginia-based company under McDonnell’s expressed priority “to promote the matter and cause of economic development for businesses and industries in Virginia.” McDonnell’s campaign slogan was, “Bob’s for Jobs.”

Star Scientific had been struggling as of late due in part to action by the U.S. Food and Drug Administration questioning the company’s marketing of their two major products: Anatabloc, “anti-inflammatory support of the immune system,” and CigRx, for smoking cessation. These concerns culminated with an exhaustively-documented FDA warning letter to Williams and Star Scientific dated December 20, 2013.

What is anatabine and what does it do?

The supplement product lines contain a naturally-occurring chemical called anatabine, a close relative of nicotine. Anatabine is a minor component of tobacco and has been used as a biomarker for tobacco use in human studies of nicotine patches for smoking cessation. Anatabine is also found in plants from the Solanaceae family, food plants such as tomatoes, peppers, cauliflower, eggplants and potatoes.

Anatabine is certainly an interesting chemical from a pharmaceutical standpoint. In vitro data with human blood and in vivo mouse studies indicate that it can inhibit the production of cytokines triggered by inflammatory stimulators by preventing activation of a transcriptional regulatory protein called STAT3. What’s not known is whether anatabine would reach these active concentrations in people who take the supplements. But that’s what a Phase I clinical trial is for, something that’s not required for dietary supplements.

In October, results from a human trial of anatabine (oddly promised in a press release last January) were published online in the Journal of Clinical Endocrinology and Metabolism. Rock Creek-funded a nine-site, placebo-controlled clinical trial of three-times-daily anatabine in 165 patients with Hashimoto’s thyroiditis.

The responses varied wildly across individual patients: “Mean ± SD TgAb values decreased by 46.2 ± 101.1 and 3.9 ± 83.9 World Health Organization units for the anatabine and placebo groups, respectively.” But a significantly higher number of anatabine-treated subjects experienced a ≥20% decrease in anti-thyroid antibodies relative to the placebo group. However, 36% of patients reported dizziness even though researchers started with a low dose to prevent this nicotinic side effect.

Hashimoto’s, or chronic lymphocytic autoimmune thyroiditis, was the first autoimmune disease described and is characterized by antibody-mediated attack of the thyroid gland. The rationale for the study was that tobacco smokers and airline flight attendants exposed occupationally to tobacco smoke back in the old days experience Hashimoto’s thyroiditis at lower incidence than the total population. These observations led researchers to hypothesize that something in tobacco smoke might protect individuals from this thyroid disease.

The accounts of this work are tangled, and were misstated in earlier versions of this article. Some Star-sponsored work on anatabine in mice had been published by Johns Hopkins University’s Dr. Paul W. Ladenson, director of their division of endocrinology, metabolism and diabetes. He also commented in a Star press release about human studies of the drug he was not involved in. The Street’s Adam Feuerstein charged that Star Scientific had inappropriately promoted their human trial as being associated with Hopkins. Feuerstein wrote a scorching review of that episode last January. A lawsuit has been filed alleging wrongdoing by Star Scientific; the company denies any wrongdoing.

(Star Scientific’s VP of Communications and Investor Relations Tahlia Tuck reminded me that Dr. Ladenson was involved in the ASAP trial, not as a site director but in the capacity of “senior endocrinological consultant for the study,” as described in their January 7, 2013 press release.)

Ladenson’s work was supported by private philanthropy so I took a look at NIH’s grants database to see if the nation’s medical research agency has funded any work on anatabine as a therapeutic agent. Thus far, only three investigators have received support for anatabine work, all from the National Institute on Drug Abuse and only as a biomarker in smoking cessation studies (Dr. Sharon M. Hall, UCSF, 2001-2008; Dr. Stephen S. Hecht, University of Minnesota, 2004-2008; and Dr. Cheryl Ann Oncken, University of Connecticut, 2002, 2006).

Sorry – it’s a drug, not a supplement

From a regulatory standpoint, Star Scientific seems to have begun digging their grave since 2010 when they began citing scientific studies of anatabine, done mostly in rodents, to make drug claims for their products on their website. Moreover, they were marketing their products under dietary supplement claims that anatabine was a naturally-occurring food constituent.

However, the December 20th FDA warning letter states,

To the best of FDA’s knowledge, there is no information demonstrating that anatabine has been present in the food supply as an article used for food in a form in which the food has not been chemically altered. Although anatabine is present as an inherent constituent of foods such as cauliflower, eggplant, potatoes, and tomatoes, FDA is not aware of any information indicating that anatabine itself is an article used for food. In the absence of such information, anatabine is a new dietary ingredient subject to the premarket notification requirement in section 413(a)(2) of the Act [21 U.S.C. § 350b(a)(2)] and 21 CFR 190.6.

As such, the FDA has ruled that Anatabloc and CigRx are adulterated with an unapproved drug, particularly since an unidentified firm had filed an Investigational New Drug application (IND) with the FDA in June, 2012. The sponsor isn’t Star Scientific or Rock Creek because they are still only talking about filing an IND as of their shareholder meeting at the end of last year. When I contacted FDA for information on the IND sponsor, media officer Juli Putnam reminded me,

The FDA cannot comment on any current/pending product applications. The FDA is only able to provide information on approved drug product applications. Any information on an application that has yet to receive an approval or was denied approval belongs to the manufacturer/sponsor developing the drug (21 CFR 314.430).

Star Scientific and their subsidiary, Rock Creek Pharmaceuticals, did themselves no favors when they promoted Rock Creek’s U.S. patent for an “improved method of synthesizing anatabine that facilitates large scale commercial production of high purity anatabine (U.S. Patent No. 8,207,346). And just in October, they were awarded another U.S. patent for the citrate salt of anatabine, the form of the drug in their products.

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I hope you will allow me to comment extensively on your article, as you seem interested in the matter of the supplements, refreshingly almost, but not quite, to the exclusion of the sensationalism surrounding the self-inflicted troubles of certain VA pols. I will comment in parts due to time limitations today and due also to the length of my comments. I will comment following direct quotes of your material.

[quote] “Star Scientific had been struggling as of late due in part to action by the U.S. Food and Drug Administration questioning the company’s marketing of their two major products …” [endquote]

You may charge “nit picking”, but “had been struggling as of late [re FDA action]” is not true, temporally speaking, with regard to the problems the McDonnells created for themselves (by not reporting apparently legal gifts to them by Williams, who is NOT indicted for any cause). The FDA action became known, as you say, only a month ago, long after the actions by the McDonnells causing their indictments by Federal authorities. Thus there is no connection between “ struggling” and Williams dealings with the McDonnells. In fact Williams had been a political contributor to and supporter of McDonnell at least since 2009, and the first anatabine supplement, by Star, was not first marketed until the end of August 2010.

The company in fact had been having nicely increasing sales of its supplements (because they work, and in many cases work minor, at the least, miracles) since their release to market.

[quote] “What’s not known is whether anatabine would reach these active concentrations in people who take the supplements. But that’s what a Phase I clinical trial is for, something that’s not required for dietary supplements.” [endquote]

This IS known (if such can be extrapolated from evident anti-inflammatory [AI] action “in people who take the supplements”). I will tell you how in (very) brief. If you want more detail please let me know.

The first anatabine supplement, CigRx, was released at the end of August 2010. It was characterized only as a “reduce smoking aid”. There had never been any talk ANYWHERE, publicly or in research, about anatabine having any anti-inflammatory (AI) properties at that time.

Some persons, including me, began taking the supplement after its release and discussing the matter online. After a couple of months, we began to talk to each other about what must be termed (in anyone’s “book”) some pretty amazing positive effects from the supplement, with no expectations of such and no reason to expect such. The list is long and includes improvements in arthritic joints, asthma, colon problems, serious back and other deep-muscular pain, (male) BPH, etc. Many of us were hesitant to attribute the difference to the anatabine supplement, but yet as months passed, many of us did the obvious and quit the supplement and observed the return of the abated symptoms.

We began writing the company about this phenomenon. I don’t think any of us heard back. It became obvious why, months later, when the company began to slowly publicize its own findings, that was true. Apparently the researchers, both in the company and without, at Roskamp Institute for example (and others associated with the company, specifically Williams) who had done the pre-clinical safety studies had also tried the supplement and had observed (in at least some) the same sorts of results. The matter was kept completely quiet for obvious (patent) reasons … thus our independent “discovery” of the phenomenon “online”.

And so your “What’s not known …” statement is not strictly true. It IS known, by some at least, from the experiences of two distinct groups of “subjects”, each group of which knew nothing about the experiences of those in the other group, and apparently the relief of inflammatory issues in the group comprising researchers, company personnel, and associates was just as much a surprise to them as it was to our independent group of discoverers.

It must be noted that these results were achieved, in me for example, with an intake of as little as one milligram of anatabine per day (three CigRx tablets), agreeing (we now know) with the in vitro studies done at Roskamp showing that anatabine’s AI property was very powerful indeed. (Your article seems to indicate you have discovered very little of the extensive research that both Star and Roskamp have done on anatabine.)

While not strictly scientific in nature, if you combine those experiences with the now tens of thousands of similar anecdotal reports from across the nation, there is certainly some credible evidence that an AI effect “in people who take the supplements” is “known”. It has been said that the plural of “anecdote” is “data”. Furthermore, you failed to report on a study (not double blind) of anatabine supplementation in heavy smokers reported (by Star) in January of 2012 that showed significant reduction of the C-RP inflammatory marker in those taking the supplement v. not.

There is much moch more to be said, but …

[quote] However, 36% of patients reported dizziness even though researchers started with a low dose to prevent this nicotinic side effect. [endquote]

Having given the paper a lot of thought, I have a lot to comment on in this regard, if I may (much of it here, but not all by any means), about the side effect reports. One must look carefully at Table 1 in the thyroid study peer-reviewed publication in the JCEM (J Clin Endocrin Metab. First published ahead of print October 31, 2013 as doi:10.1210/jc.2013-2951)

In that table one finds that in the placebo group a whopping 44% reported side effects (related or not related to the study) also, suggesting that either the study group might be prone to reporting “symptoms” when they may be either imagined or insignificant. Most remarkably, 13% of the PLACEBO group reported “Moderate or Severe Treatment-Related AE”. Something strange would seem to be going on here. I think analysis of the overall situation reveals some of what that may be.

First, I hate to say it (and do so stating my great love and respect for our truly better halves) but one possible explanation for this may IN PART be that ” Patients were predominantly female … (Supplemental Table 2).”

It is well known by those of us on both sides of that fence that males are for several reasons less likely to report minor symptoms (males are famous for not reporting them until it’s “ too late”). Add to that the fact that “getting the doctor’s ear” for such reports was free. The ratio M/F was likely very high, as the ratio of Hashimoto’s in M/F populations is something like 8:1

In another vein, one thing that may help to explain elevated reports of side effects IN BOTH the treated and placebo groups is that mannitol (a sugar/food flavoring) was in both the treated and placebo test material. It has been reported in several forums that people have written to the company reporting their own known problems with intake of the substance mannitol, which is used in all tablet form Anatabloc to this time. The company has said it is working on this (apparently a version with no additions, including the micro-doses of vitamins A and D).

It is most germane that many Internet sources list the main side effects of this common food flavoring, mannitol, to be, in order of occurrence, “headache, dizziness, nausea, and paresthesia (tingling feeling)”.

Guess what the most reported side effects were in the study: “dizziness, nausea, headache, and paresthesia” … BOTH in anatabine AND PLACEBO takers (except no paresthesia in placebo).

When comparing this study to Anatabloc supplement use, one must keep in mind that the doses of anatabine in the study were from 50% to 100% higher than the recommended supplement intake.

In the end, if one looks carefully at the study’s results and circumstances one can see that, because of such matters (the much higher doses and perhaps the predominant female participant factor, “mannitol”, etc), the study is not a good indication of side effects in normal supplement use. Even not considering this, the side effects are usually mild and amenable to dose adjustment and “working up to” a desired dose. Those who are not tobacco-naive rarely have any side effect experience at all, and I have seen no anecdotal reports of persons reporting success with supplementation who also “had to quit” because of side effects.

I have much more to comment upon, but time (and likely space) dictate that I do so separately, probably within 24 hours. Thank you for the opportunity to try to contribute to what is known about, and accurately stated about, this remarkable supplement.

In that table one finds that in the placebo group a whopping 44% reported side effects (related or not related to the study) also, suggesting that either the study group might be prone to reporting “symptoms” when they may be either imagined or insignificant, or that there is something in common with the “treatment” and the placebo compounds that can cause problems.

Well, since you have the paper, you can see that there’s an awful lot going on in the placebo group. Almost 30% of those in the placebo group experienced a @0% or greater decline in TgAb. So while you see side effects in the placebo group, you also see some efficacy.

I will comment next and in isolation on what must be one of the worst “reference” pieces since the invention of the written word, the Feuerstein piece to which the Kroll article referred.

[quote] Star Scientific had inappropriately promoted their trial as being associated with Hopkins but was merely commented upon by Ladenson, a paid consultant. The Street’s Adam Feuerstein wrote a scorching review of that episode last January. [endquote]

I invite Mr. Kroll or anyone to cite actual evidence cited in Feuerstein’s (AF) hit piece of what “Star” said to make what AF termed Star’s made up relationship between the thyroid (ASAP) study and Johns Hopkins (JH). IT IS NOT THERE. IN FACT, AF’s ONLY reference to what “Star” said was that Star FAILED TO make that connection in a press release when it had the opportunity to do so. That FAILURE to make the study-JH connection was, INCREDIBLY, cited by Feuerstein as “suspicious”, and THAT is as far as Feuerstein went in supposedly illustrating Star’s attempt to associate JH with the ASAP study!

I will now quote Star’s reply, in press and in print, to Feuerstein’s hit piece. Somehow all of you who write about this matter seem to find the Feuerstein article just fine, but none of you is able to find, apparently, Star’s concise, accurate and vanquishing reply. Well, here it is:

[quote] Star Scientific, Inc. Refutes Story Published on TheStreet.com

As reported in the Company’s January 7, 2013, press release: “The preliminary examination of the primary outcomes shows a clear and statistically significant difference in the treated group as compared to the placebo group by the end of the trial, with declines in anti-thyroglobulin antibody levels. Anatabine subjects also tended toward a reduction in thyroid gland vascularity on ultrasound relative to placebo.” The ASAP study, which examines the impact of anatabine dietary supplementation on thyroid health, was conducted by Rock Creek Pharmaceuticals, the Company’s subsidiary. The study was not sponsored by the Johns Hopkins School of Medicine, and the Company never reported otherwise. Indeed, when Star Scientific first announced IRB approval of this study on February 9, 2012, it noted that the study was being conducted by Rock Creek Pharmaceuticals at sites in Texas, Illinois, and Florida. The Company also consistently referenced that this study was being conducted by Rock Creek Pharmaceuticals at multiple sites in subsequent press releases, including the January 7, 2013, release. Any implication by the author of the article in TheStreet.com that Star Scientific stated otherwise is patently false.

The statement that there is no science backing that anatabine reduces inflammation similarly is completely false. Since 2011, Rock Creek Pharmaceuticals and researchers at the Roskamp Institute have completed and reported on a number of studies designed to assess the ability of the Company’s anatabine compound to lower chronic inflammation in a variety of pre-clinical (non-human) and clinical (human) settings. One study conducted by the Roskamp Institute and reported in The Journal of European Pharmacology in 2011 showed that anatabine lowered levels of amyloid production both in the test tube and when administered to mice vulnerable to accumulation of amyloid which, at excessive levels damages brain tissue. A second manuscript written by the same researchers and published online in The Journal of European Pharmacology in 2012 and in manuscript form in January 2013 further characterized the anti-inflammatory effects of anatabine in several types of animal tissues, in human cells, and in human whole blood. The Roskamp Institute also presented results of pre-clinical studies of anatabine in mouse models of multiple sclerosis, traumatic brain injury, and Alzheimer’s disease at the Neuroscience 2012 conference held in New Orleans in October 2012.

In January 2012, Rock Creek Pharmaceuticals reported research on the first clinical trial demonstrating that Anatabloc® lowers chronic inflammation measured by CRP levels in the blood. The reported results were obtained in connection with an in-house study undertaken by Rock Creek that involved a group of smokers who had been using Anatabloc® on an extended basis. In October 2012, Rock Creek reported on an interim look at the CRP results in a study sponsored by the Roskamp Institute and designed to assess the safety, tolerability, dosing, and biological effects of anatabine citrate. Currently, a clinical study of individuals with mild to moderate Alzheimer’s disease is being sponsored by Rock Creek Pharmaceuticals and conducted at the Roskamp Institute.

Prior to the introduction of the Company’s first dietary supplement, research scientists at Harvard University’s McLean Hospital completed extensive research, which was funded by Rock Creek Pharmaceuticals, relating to the safety of anatabine as well as its non-nicotinic effects in connection with development of the product.

Furthermore, The Street.com article’s implication or suggestion that Johns Hopkins has had no involvement in anatabine research is also false. As previously reported, a preclinical investigator-initiated and independently funded study from Johns Hopkins examined the effect of anatabine supplementation on autoimmune thyroiditis in a mouse model and that research was recently published in an article entitled, “Anatabine Ameliorates Experimental Autoimmune Thyroiditis” in the Endocrine Society’s journal, Endocrinology. (Endocrinology. 2012 Sep; 153(9):4580-7.) All three of the published articles referenced in this press release were peer reviewed anonymously by experts in the field chosen by the editors of the journals.

Star Scientific notes that the author of the article in TheStreet.com, Adam Feuerstein, has published a number of negative articles regarding the Company and its research on anatabine. The Company believes that investors and consumers of its Anatabloc® product would be well advised to view any such articles by this author or publications regarding the Company in TheStreet.com with substantial skepticism, given the misstatements and misinformation that the author disseminates.

Star Scientific takes its responsibilities to provide and present accurate information about and to respond to false statements about its products very seriously. This press release and communications that are being sent to The Street and its author by Star Scientific’s attorneys are examples of that effort. [endquote]

You notice that this release references the Jan 2012 study I cited in my first reply to the Kroll article.

Rather than being a “review” of “that episode”, there BEING NO “EPISODE”, Feuerstein’s hit peice was simply a declaration of war, apparently by short interests in the stock, on the company. The only thing that was “made up” was Feuerstein’s supposed ammunition re Star, as opposed to his gripes about what “Internet stock promoters”, beyond Star’s control, said and did. The suspicious thing in many minds is that everyone pays attention to AF’s account, and none ever mentions the facts, not only undisputed but unnoticed, cited by Star in the above piece. The question is, “Why?” Did you, Mr. Kroll, make any attempt at a search for such material?

Your “correction” was/is WRONG. SHOW A QUOTE of any material from ANY Star press release that suggests that “the study” (thyroid) was done at JH. Why do you keep avoiding the simple expediency of showing an actual quote of Star?? You are simply, flatly WRONG.

ive been on product over 2 and a half years now! Im my own experiment! I wont go into the benefits but as a writer you should ask your self how does a co. like this generate 10mil in sales on a dietary supplement that has an over 60% reorder ratio! its a fantastic supplement! you all did a great job ripping the company again however the science will prevail and before you know it the secret will come out that anatabine is the real deal. oh and google parkinsons and peppers… maybe that will help you on how this story will unfold

Plenty of companies make profits on the placebo effect. But I’m more willing than many pharm writers to give natural products a fair benefit of the doubt. I’m sorry you viewed this piece as ripping the company. I thought I tried to be somewhat thorough on the actual science.

I completely agree with Mr. There’s comments. My family and I have used Anatabloc for about a year and a half. I was turned on to Anatabloc by some friends while shopping for running shoes. I gave it a try, because my knees had been killing from running and jumping out of airplanes. The military usually gives us 800mg Motrin, but after a while it’s hard on your stomach and intestines. So I began taking Anatabloc. Less than a week later my knees where not as sore. I continue to take Anatabloc and the small aches and pains are not as severe. Also, my Blood Pressure has been lowered greatly. Again, these are my accounts. My mother recently fell down our steps and broke her hip, I supplied her with one of my bottles after she complained about the swelling. She said it did help; enough said. After seeing the implications or reactions to Anatabloc I decided to invest in the company. I do play the market on occassion, and do my own research as well. So, I get a little concerned when people who are paid to right objective articles fail to do any real research on the subject matter. Ben has stated the medical drama with AF, so I will not retort. I would like to talk about the massive manipulation in this company. Recently, 68k call options with a $1 strike where purchased for .05 cents which is an unusually large amount for a company that has less than a $200 million dollar market cap. Seems a little fishy, OK, I’ll bite. Then, this company is getting hammered from all sides of the Business world with slanted articles and hedge funds alike. So braisen was one hedge fund they had the chemical compound placed on a quilt and sent to Adam Furestein. The only assumption here, it was a thank you for the slanderous article that knocked the stock price down. So Mr. Kroll, there must be something to this product if the Short Interest (23 Million shares) and the news agencies are hammering this very small cap stock as if it where the only small cap in the NASDAQ. Another issue was an article written 3 years ago by Bloomberg that the stock was being delisted due to compliance issues of the stock being lower than $1 for 30 straigt days. The stock was at $5 and rising, again the article contributed to the stock price being hammered; Again I ask why? As of yesterday I have learned that Black Rock just filed a 13G purchasing an additional 5+Million Shares and announcing a greater than five percent stake in the company. Then your article comes out. Again, Mr. Kroll, just something that makes you say HUMMMMMM!

Mr. Kroll, one last comment; If you frequently write about drugs for Forbes, you should have already known that the FDA will not respond to anyone regarding information about the status of an investigational new drug application. So this tells the reader that a) you do not understand the FDA process regarding INDs, therefore you probably should not be writing about drugs; b) you knew already that the FDA would not provide that informationbut made it seem as if you really did some investigative work regarding this information; or c) you called thinking you were the exception to the rule for retreiving information that would benefit the readers (Hedge Funds, short interest, etc. Lastly, I would actually like to thank you, because of your article it allows folks like Ben and I to respond with actual facts and research that the reader may not otherwise have known. Enjoy your day sir! If they did every investment house and investor would be calling non-stop for information to get an upper hand. So what you had done is actually against SEC regulations.

D.E. Smith, I was trying to anticipate questions like that above from “Ben There.” I certainly know that FDA cannot disclose IND filings but was hoping to at least get confirmation that Star Scientific or Rock Creek were not the sponsors.

Thank you for furthering the understanding of Anatabloc in the Medical community. You seem to have a good start in understanding Anatabloc, but I strongly encourage you to do some additional investigative medical reporting.

Many of us would like some additional color to the following questions:

1) Why did a world renowned Alzheimer expert (Michael Mullan) agree to take over as CEO at Star Scientific? This says a lot about his faith in the science already completed regarding Anatabine.

2) Why did Dr. Paul Landenson, a noted John Hopkin’s endocrinologist agree to lead an anatabine study funded in large part by the Walton Foundation?

3) How many complaints has the FDA received from consumers since Anatabloc went on sale over 2 years ago? Seems recent reports regarding side effects may be exagarated as the Thyroid study used 2x the normal recommended dosage on the Anatabloc bottle and dosages were then adjusted. I would like to know how many complaints that the general population has submitted to the FDA.

Please help us separate the anatabine science from all the political and legal turmoil recently.